http://www.biospace.com/news_story.aspx?StoryID=359717&full=1
"Imaginary Meal" Tricks The Body Into Losing Weight
Salk scientists made a more effective diet pill
LA JOLLA–Salk researchers have developed an entirely new type of pill that tricks the body into thinking it has consumed calories, causing it to burn fat. The compound effectively stopped weight gain, lowered cholesterol, controlled blood sugar and minimized inflammation in mice, making it an excellent candidate for a rapid transition into human clinical trials.
~~~~
Evans and his colleagues developed the fexaramine compound by departing from the drug scaffold that most pharmaceutical companies typically pursue when targeting FXR. “It turns out that when we administer this orally, it only acts in the gut,” explains Michael Downes, a senior staff scientist at Salk and co-corresponding author of the new work. Giving one such drug in a daily pill form that only reaches the intestines–without transporting into the bloodstream that would carry the drug throughout the body–not only curtails side effects but also made the compound better at stopping weight gain.
When the group gave obese mice a daily pill of fexaramine for five weeks, the mice stopped gaining weight, lost fat and had lower blood sugar and cholesterol levels than untreated mice. In addition, the mice had a rise in body temperature–which signals metabolism ramping up–and some deposits of white fat in their bodies converted into a healthier, energy-burning beige form of the tissue. Even the collection of bacteria in the guts of mice shifted when they received the drug, although what those changes mean isn’t clear yet.
This is the original paper: http://www.ncbi.nlm.nih.gov/pubmed/25559344
Nat Med. 2015 Jan 5. doi: 10.1038/nm.3760. [Epub ahead of print]
Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance.
Fang S1, Suh JM1, Reilly SM2, Yu E1, Osborn O3, Lackey D3, Yoshihara E1, Perino A4, Jacinto S1, Lukasheva Y1, Atkins AR1, Khvat A5, Schnabl B3, Yu RT1, Brenner DA3, Coulter S6, Liddle C6, Schoonjans K4, Olefsky JM3, Saltiel AR2, Downes M1, Evans RM7.
Author information
Abstract
The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver. However, unlike systemic agonism, we find that Fex reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue (WAT). These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome.
If anyone has access to this paper, I'd like to read it. Enhancing of thermogenesis is behind my theory (that I've had for 35+ years) that obesity could be treated by making obese people burn off excess calories like normal people do, releasing the energy as heat, which process is mediated by brown adipose tissue, that obese people lack. That way, we'd be both thin AND warm.
Here's a proof of concept paper:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4016120/
Nature. Author manuscript; available in PMC Nov 8, 2014.
Published in final edited form as:
Nature. May 8, 2014; 509(7499): 183–188.
Published online Mar 26, 2014. doi: 10.1038/nature13135
PMCID: PMC4016120
NIHMSID: NIHMS566183
FXR is a molecular target for the effects of vertical sleeve gastrectomy
Karen K. Ryan,1 Valentina Tremaroli,2 Christoffer Clemmensen,1,3 Petia Kovatcheva-Datchary,2 Andriy Myronovych,4Rebekah Karns,5 Hilary E. Wilson-Pérez,1 Darleen A. Sandoval,1 Rohit Kohli,4 Fredrik Bäckhed,2,6 and Randy J. Seeley1
Author information ► Copyright and License information ►
The publisher's final edited version of this article is available at Nature
See other articles in PMC that cite the published article.
Go to:
SUMMARY
Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are currently the most effective therapy for the treatment of obesity, and are associated with substantial improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering tremendous potential to reveal new targets for therapeutic intervention. The present study demonstrates that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach. Rather, we report that VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities. Moreover, in the absence of nuclear bile acid receptor FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. These results point to bile acids and FXR signaling as an important molecular underpinning for the beneficial effects of this weight-loss surgery.
"Imaginary Meal" Tricks The Body Into Losing Weight
Salk scientists made a more effective diet pill
LA JOLLA–Salk researchers have developed an entirely new type of pill that tricks the body into thinking it has consumed calories, causing it to burn fat. The compound effectively stopped weight gain, lowered cholesterol, controlled blood sugar and minimized inflammation in mice, making it an excellent candidate for a rapid transition into human clinical trials.
~~~~
Evans and his colleagues developed the fexaramine compound by departing from the drug scaffold that most pharmaceutical companies typically pursue when targeting FXR. “It turns out that when we administer this orally, it only acts in the gut,” explains Michael Downes, a senior staff scientist at Salk and co-corresponding author of the new work. Giving one such drug in a daily pill form that only reaches the intestines–without transporting into the bloodstream that would carry the drug throughout the body–not only curtails side effects but also made the compound better at stopping weight gain.
When the group gave obese mice a daily pill of fexaramine for five weeks, the mice stopped gaining weight, lost fat and had lower blood sugar and cholesterol levels than untreated mice. In addition, the mice had a rise in body temperature–which signals metabolism ramping up–and some deposits of white fat in their bodies converted into a healthier, energy-burning beige form of the tissue. Even the collection of bacteria in the guts of mice shifted when they received the drug, although what those changes mean isn’t clear yet.
This is the original paper: http://www.ncbi.nlm.nih.gov/pubmed/25559344
Nat Med. 2015 Jan 5. doi: 10.1038/nm.3760. [Epub ahead of print]
Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance.
Fang S1, Suh JM1, Reilly SM2, Yu E1, Osborn O3, Lackey D3, Yoshihara E1, Perino A4, Jacinto S1, Lukasheva Y1, Atkins AR1, Khvat A5, Schnabl B3, Yu RT1, Brenner DA3, Coulter S6, Liddle C6, Schoonjans K4, Olefsky JM3, Saltiel AR2, Downes M1, Evans RM7.
Author information
Abstract
The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver. However, unlike systemic agonism, we find that Fex reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue (WAT). These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome.
If anyone has access to this paper, I'd like to read it. Enhancing of thermogenesis is behind my theory (that I've had for 35+ years) that obesity could be treated by making obese people burn off excess calories like normal people do, releasing the energy as heat, which process is mediated by brown adipose tissue, that obese people lack. That way, we'd be both thin AND warm.
Here's a proof of concept paper:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4016120/
Nature. Author manuscript; available in PMC Nov 8, 2014.
Published in final edited form as:
Nature. May 8, 2014; 509(7499): 183–188.
Published online Mar 26, 2014. doi: 10.1038/nature13135
PMCID: PMC4016120
NIHMSID: NIHMS566183
FXR is a molecular target for the effects of vertical sleeve gastrectomy
Karen K. Ryan,1 Valentina Tremaroli,2 Christoffer Clemmensen,1,3 Petia Kovatcheva-Datchary,2 Andriy Myronovych,4Rebekah Karns,5 Hilary E. Wilson-Pérez,1 Darleen A. Sandoval,1 Rohit Kohli,4 Fredrik Bäckhed,2,6 and Randy J. Seeley1
Author information ► Copyright and License information ►
The publisher's final edited version of this article is available at Nature
See other articles in PMC that cite the published article.
Go to:
SUMMARY
Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are currently the most effective therapy for the treatment of obesity, and are associated with substantial improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering tremendous potential to reveal new targets for therapeutic intervention. The present study demonstrates that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach. Rather, we report that VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities. Moreover, in the absence of nuclear bile acid receptor FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. These results point to bile acids and FXR signaling as an important molecular underpinning for the beneficial effects of this weight-loss surgery.
